Repeated exposure to psychostimulants or stress produces a progressive and enduring increase in psychostimulant-induced locomotor activity in rodents, a phenomenon referred to as behavioral sensitization. Extracellular dopamine levels in the nucleus accumbens are enhanced in rats sensitized to stress or cocaine, while extracellular dopamine levels in the medial prefrontal cortex (mPFC) are diminished. Thus, dopamine in the mPFC demonstrates tolerance rather than sensitization in response to a subsequent cocaine or stress challenge. Since dopamine in the mPFC inhibits mPFC excitatory amino acid (EAA) efferents to subcortical sites and produces inhibition of stimulated locomotion, recent studies in this laboratory determined whether the tolerance of mPFC dopamine responsiveness to cocaine or stress may contribute to sensitization of locomotor activity. The effects of intra-mPFC microinjection of d-amphetamine on cocaine-stimulated locomotor activity was measured in control and cocaine sensitized rats, and the results suggest an important contribution by the mPFC for the expression of cocaine sensitization. The experiments are designed to test the hypotheses that 1) tolerance of the mPFC dopamine response in sensitized rats contributes to the expression of behavioral sensitization, and this response may be importantly modulated by glutamate in the mPFC, and 2) repeated stress and/or cocaine pretreatment alter the ability of dopamine agonists administered into the mPFC to regulate subsequent cocaine-induced activity. The proposed work will examine regulation of the expression of stress- and cocaine-induced behavioral sensitization by the mPFC with emphasis on regulation of mPFC dopamine tolerance and its contribution to behavioral output. For all studies, the treatment groups will be naive, daily sham shock, foot shock, saline or cocaine. The first specific aim focuses on the modulation of stress- and cocaine- induced tolerance of dopamine in the mPFC by glutamate. The second specific aim will examine modulation of sensitization by local administration of dopamine receptor agonists into the mPFC. The third specific aim will determine which specific pathway(s) may be altered in the regulation of behavioral sensitization to stress and cocaine with regard to EAA projections from the mPFC to the nucleus accumbens vs. those efferents from the mPFC to the ventral tegmental area (VTA). Incorporation of the mPFC circuitry into sensitization studies should lead to an increased understanding of the mechanisms by which stress predisposes individuals to initiation and reinstatement of drug taking behavior and psychoses.